The pathophysiology of diastolic heart failure.
Diastolic heart failure, also called heart failure with preserved ejection fraction, results from diastolic stiffening of the myocardium and not from reduced systolic contractile performance. In an ageing population, this form of heart failure is rapidly becoming the main heart failure phenotype observed in 60% of patients. So far, no single treatment modality has been shown to improve prognosis in diastolic heart failure.
Over the last ten years, many novel pathophysiological insights relating to diastolic heart failure have been acquired in his laboratory at VU University Medical Center:
” Recognition of high intrinsic diastolic stiffness of cardiomyocytes retrieved from patients with diastolic heart failure (Circulation 2005;111:774-781).
” Description of structural and functional differences of left ventricular myocardium between patients with diastolic and systolic heart failure (Circulation 2006;113:1966-1973), which become especially prominent in the presence of diabetes (Circulation 2008;117:52-60; Circulation. 2011;124:1151-9).
” Recognition of low phosphorylation of the giant cytoskeletal protein titin causing high cardiomyocyte stiffness in diastolic heart failure (Circ Res. 2009;104:780-6).
” Discovery of low protein kinase G activity in myocardium of diastolic heart failure patients (Circulation. 2012;126:830-9).
Based on these new insights, a novel paradigm for diastolic heart failure was developed (J Am Coll Cardiol. 2013;62:263). This paradigm recognizes metabolic comorbidities as a cause of coronary microvascular endothelial inflammation, which lowers myocardial nitric oxide bioavailability and PKG activity. The latter stiffens titin and releases the brake on myocardial hypertrophy. This paradigm is currently being validated in experimental and clinical studies.
Selection of publications
Paulus WJ, Tschöpe C, Sanderson JE, Rusconi C, Flachskampf FA, Rademakers FE, Marino P, Smiseth OA, De Keulenaer G, Leite-Moreira AF, Borbély A, Édes I, Handoko ML, Heymans S, Pezzali N, Pieske B, Dickstein K, Fraser AG, Brutsaert DL. How to diagnose diastolic heart failure ?. Eur Heart J 2007;28:2539-2550. (820)
Carabello BA, Paulus WJ. Aortic Stenosis. Lancet 2009;373:956-966. (111)
WJ. Paulus, Pascal J. Vantrimpont, Ajay M. Shah. Acute effects of nitric oxide on left ventricular relaxation and diastolic distensibility in man. Circulation. 1994;89:2070-2078. (270)
van Heerebeek L, Borbely A, Niessen HWM, Bronzwaer JGF, van der Velden J, Stienen GJM, Linke WA, Laarman GJ, Paulus WJ. Myocardial structure and function differ in systolic and diastolic heart failure. Circulation 2006;113:1966-1973. (202)
Ongoing research projects
European Commission FP7 Health Large Collaborative Project on Diastolic Heart Failure (MEDIA: The Metabolic Road to Diastolic Heart Failure); CVON-ARENA: RNA mechanisms in heart failure.